Presently, the most commonly used agents for preventing and treating rejection phenomena associated with organ and tissue transplantations, graft-versus-host diseases and autoimmune diseases are immunosuppressive drugs, e.g. cyclosporin A (CsA), FK506, azathioprine (AZ), methotrexate (Mtx), rapamycin (R), mycophenolate mofetil (Mac) and glucocorticosteroids (Gluc).
All these drug therapies are limited in effectiveness, in part because the doses needed for effective treatments may increase the patient's susceptibility to infection by a variety of opportunistic invaders and, mainly, because of the side effects caused by its direct toxicity. For instance, despite various successful results, a serious limitation to the wider application of CsA in these indications is the toxicity of this substance. In the first place, its marked nephrotoxicity which in some cases is irreversible has to be mentioned here, but also other phenomena such as hypertension, nausea, diabetes, diarrhoea, tremor, tingling or gingival hypertrophy (Palestine A.R. et al.: Am.J.Med. 77 (1984), 652-656), and lymphomagenesis represent complications to be taken seriously, which usually cannot be avoided even with systematic checking of the serum level. In addition, opportunistic infections have to be considered (Dawson T. et al.: J. Rheumatol. 19 (1992), 997), so that by critical benefit-risk assessment an otherwise advantageous CsA medication in many cases has to be sacrificed. FK506 (Tacrolimus) is a macrolide which exerts largely similar effects as CsA, both with regard to its molecular mode of action and its clinical efficacy (Liu J.: Immunol. Today 14 (1993), 290-295; Schreiber S.L. et al.: Immunol. Today 13 (1992), 136-142); these effects, however, may be found already at doses which are less by the factor 20 to 100 compared to CsA (Peters D.H. et al.: Drugs 46 (1993), 746-794). The same is true for rapamycin (R) which again is a macrolide binding intracellularly to the same immunophilin as FK506, although the following biochemical events are differing somewhat (Morris R.E.: Transplant. Rev. 6 (1992), 39-87).
Accordingly, it would be desirable to have a drug capable of potentiating the action of currently used immunosuppressive agents. Ideally, such a drug would increase the efficacy of such immunosuppressive agents and also decrease deleterious side-effects by allowing administration of lower dosage levels.
After an extensive study on the possibility that the effect of an immunosuppressive agent (A) in the present invention is improved by combining it with a variety of compounds, the present inventor has surprisingly discovered that the effect of an immunosuppressive agent (A) is significantly improved and side-effects can be decreased by co-administering it with at least one 2,2'-bi-1H-pyrrole compound (B), as herein defined.
2,2'-Bi-1H-pyrrole compounds (B), according to the present invention are immunosuppressive agents which are known, e.g., from WO 95/17381. Such description also shows a combined use of an immunosuppressant agent (A) and a 2,2'-bi-1H-pyrrole compound (B), in immunosuppressive therapy. However, WO 95/17381 neither shows, nor suggests, that said combined use cause synergistic increase in effect or decrease side-effects in immunosuppressive therapy. In particular, WO 95/17381 neither shows, nor suggests, that the same therapeutic effect obtainable by the combined use of therapeutically effective amounts of an immunosuppressant agent (A) and a 2,2'-bi-1H-pyrrole compound (B) can be similarly also obtained by co-administration of doses by itself inactive of the same two immunosuppressant agents (A) and (B).